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Anti-estrogen Resistance in Human Breast Tumors Is Driven by JAG1-NOTCH4-Dependent Cancer Stem Cell Activity.

Simões BM, O'Brien CS, Eyre R, Silva A, Yu L, Sarmiento-Castro A, Alférez DG, Spence K, Santiago-Gómez A, Chemi F, Acar A, Gandhi A, Howell A, Brennan K, Rydén L, Catalano S, Andó S, Gee J, Ucar A, Sims AH, Marangoni E, Farnie G, Landberg G, Howell SJ, Clarke RB - Cell Rep (2015)

Bottom Line: Here, we show that short-term treatment with the anti-estrogens tamoxifen or fulvestrant decrease cell proliferation but increase BC stem cell (BCSC) activity through JAG1-NOTCH4 receptor activation both in patient-derived samples and xenograft (PDX) tumors.In support of this mechanism, we demonstrate that high ALDH1 predicts resistance in women treated with tamoxifen and that a NOTCH4/HES/HEY gene signature predicts for a poor response/prognosis in 2 ER+ patient cohorts.Targeting of NOTCH4 reverses the increase in Notch and BCSC activity induced by anti-estrogens.

View Article: PubMed Central - PubMed

Affiliation: Breast Cancer Now Research Unit, Institute of Cancer Sciences, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK.

No MeSH data available.


Related in: MedlinePlus

NOTCH4 Receptor Activity Predicts for Resistance to Tamoxifen Treatment and Prognosis in ER+ Tumors(A and B) NOTCH4, HES1, HEY1, and HEY2 genes in ER+ primary tumors from (A) tamoxifen-treated or (B) untreated patients are co-expressed in the heatmap ranked from left to right using the four-gene signature. Colors are log2 mean-centered values; red indicates high, and green indicates low. All significant cut-points (p < 0.05) are shown in gray. Kaplan-Meier analysis using the optimum cut-point (dashed white line) demonstrates that elevated expression of the Notch genes is significantly associated with an increased rate of (A) distant metastasis and (B) decreased overall survival. Vertical bars on survival curves indicate censored cases. p values are based on a log-rank (Mantel-Cox) test.(C) Diagram suggesting that endocrine therapies do not target BCSCs and emphasizing the need of targeting residual drug-resistant cells to eliminate all cancer cells and prevent long-term recurrences of ER+ BC.
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fig5: NOTCH4 Receptor Activity Predicts for Resistance to Tamoxifen Treatment and Prognosis in ER+ Tumors(A and B) NOTCH4, HES1, HEY1, and HEY2 genes in ER+ primary tumors from (A) tamoxifen-treated or (B) untreated patients are co-expressed in the heatmap ranked from left to right using the four-gene signature. Colors are log2 mean-centered values; red indicates high, and green indicates low. All significant cut-points (p < 0.05) are shown in gray. Kaplan-Meier analysis using the optimum cut-point (dashed white line) demonstrates that elevated expression of the Notch genes is significantly associated with an increased rate of (A) distant metastasis and (B) decreased overall survival. Vertical bars on survival curves indicate censored cases. p values are based on a log-rank (Mantel-Cox) test.(C) Diagram suggesting that endocrine therapies do not target BCSCs and emphasizing the need of targeting residual drug-resistant cells to eliminate all cancer cells and prevent long-term recurrences of ER+ BC.

Mentions: Based on the aforementioned observations, we hypothesized that NOTCH4 activity, comprising a NOTCH4/HES/HEY gene signature, would predict for response to tamoxifen treatment. In gene expression data from 669 pre-treatment tumors from four published Affymetrix microarray datasets of ER+ patients who subsequently received adjuvant tamoxifen therapy, we found NOTCH4, HES1, HEY1, and HEY2 to be co-expressed in some tumors, as demonstrated in the heatmap ordered from left to right by the sum of the four genes (Figure 5A). Importantly, elevated expression of these Notch genes before treatment was significantly associated with distant metastasis (Figure 5A) and with reduced overall survival in an independent cohort of 343 untreated ER+ patients (Figure 5B). Thus, NOTCH4 gene expression and activity in tumors before treatment with endocrine therapy predicts sensitivity to treatment, indicating that this signaling pathway predicts de novo as well as acquired endocrine resistance. These data strengthen the case for therapies against NOTCH4 to target the endocrine-resistant ALDH-positive cells responsible for relapse of ER+ tumors following hormonal therapy (Figure 5C).


Anti-estrogen Resistance in Human Breast Tumors Is Driven by JAG1-NOTCH4-Dependent Cancer Stem Cell Activity.

Simões BM, O'Brien CS, Eyre R, Silva A, Yu L, Sarmiento-Castro A, Alférez DG, Spence K, Santiago-Gómez A, Chemi F, Acar A, Gandhi A, Howell A, Brennan K, Rydén L, Catalano S, Andó S, Gee J, Ucar A, Sims AH, Marangoni E, Farnie G, Landberg G, Howell SJ, Clarke RB - Cell Rep (2015)

NOTCH4 Receptor Activity Predicts for Resistance to Tamoxifen Treatment and Prognosis in ER+ Tumors(A and B) NOTCH4, HES1, HEY1, and HEY2 genes in ER+ primary tumors from (A) tamoxifen-treated or (B) untreated patients are co-expressed in the heatmap ranked from left to right using the four-gene signature. Colors are log2 mean-centered values; red indicates high, and green indicates low. All significant cut-points (p < 0.05) are shown in gray. Kaplan-Meier analysis using the optimum cut-point (dashed white line) demonstrates that elevated expression of the Notch genes is significantly associated with an increased rate of (A) distant metastasis and (B) decreased overall survival. Vertical bars on survival curves indicate censored cases. p values are based on a log-rank (Mantel-Cox) test.(C) Diagram suggesting that endocrine therapies do not target BCSCs and emphasizing the need of targeting residual drug-resistant cells to eliminate all cancer cells and prevent long-term recurrences of ER+ BC.
© Copyright Policy - CC BY
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4594158&req=5

fig5: NOTCH4 Receptor Activity Predicts for Resistance to Tamoxifen Treatment and Prognosis in ER+ Tumors(A and B) NOTCH4, HES1, HEY1, and HEY2 genes in ER+ primary tumors from (A) tamoxifen-treated or (B) untreated patients are co-expressed in the heatmap ranked from left to right using the four-gene signature. Colors are log2 mean-centered values; red indicates high, and green indicates low. All significant cut-points (p < 0.05) are shown in gray. Kaplan-Meier analysis using the optimum cut-point (dashed white line) demonstrates that elevated expression of the Notch genes is significantly associated with an increased rate of (A) distant metastasis and (B) decreased overall survival. Vertical bars on survival curves indicate censored cases. p values are based on a log-rank (Mantel-Cox) test.(C) Diagram suggesting that endocrine therapies do not target BCSCs and emphasizing the need of targeting residual drug-resistant cells to eliminate all cancer cells and prevent long-term recurrences of ER+ BC.
Mentions: Based on the aforementioned observations, we hypothesized that NOTCH4 activity, comprising a NOTCH4/HES/HEY gene signature, would predict for response to tamoxifen treatment. In gene expression data from 669 pre-treatment tumors from four published Affymetrix microarray datasets of ER+ patients who subsequently received adjuvant tamoxifen therapy, we found NOTCH4, HES1, HEY1, and HEY2 to be co-expressed in some tumors, as demonstrated in the heatmap ordered from left to right by the sum of the four genes (Figure 5A). Importantly, elevated expression of these Notch genes before treatment was significantly associated with distant metastasis (Figure 5A) and with reduced overall survival in an independent cohort of 343 untreated ER+ patients (Figure 5B). Thus, NOTCH4 gene expression and activity in tumors before treatment with endocrine therapy predicts sensitivity to treatment, indicating that this signaling pathway predicts de novo as well as acquired endocrine resistance. These data strengthen the case for therapies against NOTCH4 to target the endocrine-resistant ALDH-positive cells responsible for relapse of ER+ tumors following hormonal therapy (Figure 5C).

Bottom Line: Here, we show that short-term treatment with the anti-estrogens tamoxifen or fulvestrant decrease cell proliferation but increase BC stem cell (BCSC) activity through JAG1-NOTCH4 receptor activation both in patient-derived samples and xenograft (PDX) tumors.In support of this mechanism, we demonstrate that high ALDH1 predicts resistance in women treated with tamoxifen and that a NOTCH4/HES/HEY gene signature predicts for a poor response/prognosis in 2 ER+ patient cohorts.Targeting of NOTCH4 reverses the increase in Notch and BCSC activity induced by anti-estrogens.

View Article: PubMed Central - PubMed

Affiliation: Breast Cancer Now Research Unit, Institute of Cancer Sciences, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK.

No MeSH data available.


Related in: MedlinePlus